Int. J. Med. Sci. 2014, Vol. 11
Ivyspring
International Publisher
1185
International Journal of Medical Sciences
2014; 11(11): 1185-1200. doi: 10.7150/ijms.10001
Review
Risk Factors Contributing to Type 2 Diabetes and
Recent Advances in the Treatment and Prevention
Yanling Wu1,2, Yanping Ding1,2, Yoshimasa Tanaka3 and Wen Zhang2
1.
2.
3.
Lab of Molecular Immunology, Zhejiang Provincial Center for Disease Control and Prevention, 3399 Binsheng Road, Hangzhou, 310051,
China;
Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, 18
Chaowang Road, Hangzhou, 310014, China;
Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto,
606-8501, Japan.
 Corresponding author: Yanling Wu, Lab of Molecular Immunology, Virus Inspection Department of Zhejiang Provincial Center for
Disease Control and Prevention, 3399 Binsheng Road, Hangzhou, 310051, PR China; Tel: +86-571-87115282; Fax: +86-571-87115282; e-mail:
[email protected]. Wen Zhang, Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University
of Technology, 18 Chaowang Road, Hangzhou, 310014, PR China; Tel: +86-571-88871507; Fax: +86-571-88871507; e-mail:
[email protected].
© Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/
licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.
Received: 2014.06.28; Accepted: 2014.08.01; Published: 2014.09.06
Abstract
Type 2 diabetes is a serious and common chronic disease resulting from a complex inheritance-environment interaction along with other risk factors such as obesity and sedentary lifestyle. Type 2 diabetes and its complications constitute a major worldwide public health problem,
affecting almost all populations in both developed and developing countries with high rates of
diabetes-related morbidity and mortality. The prevalence of type 2 diabetes has been increasing
exponentially, and a high prevalence rate has been observed in developing countries and in populations undergoing “westernization” or modernization. Multiple risk factors of diabetes, delayed
diagnosis until micro- and macro-vascular complications arise, life-threatening complications,
failure of the current therapies, and financial costs for the treatment of this disease, make it
necessary to develop new efficient therapy strategies and appropriate prevention measures for the
control of type 2 diabetes. Herein, we summarize our current understanding about the epidemiology of type 2 diabetes, the roles of genes, lifestyle and other factors contributing to rapid
increase in the incidence of type 2 diabetes. The core aims are to bring forward the new therapy
strategies and cost-effective intervention trials of type 2 diabetes.
Key words: type 2 diabetes, genetic factor, lifestyle, treatment, intervention trial.
Introduction
Diabetes mellitus (DM) is characterized by
chronic hyperglycemia and impaired carbohydrates,
lipids, and proteins metabolism caused by complete
or partial insufficiency of insulin secretion and/or
insulin action. There are two primary forms of diabetes, insulin-dependent diabetes mellitus (type 1 diabetes mellitus, T1DM) and non-insulin-dependent
diabetes mellitus (type 2 diabetes mellitus, T2DM).
T2DM is the most common form of DM, which accounts for 90% to 95% of all diabetic patients [1] and is
expected to increase to 439 million by 2030 [2]. In
China, the latest statistical data show that diabetes
and pre-diabetes are prevalent among people older
than 20-year-old, with the percentages being 9.7% and
15.5% for T1DM and T2DM, respectively [3]. T2DM
mostly results from the interaction among genetic,
environmental and other risk factors. Furthermore,
loss of first-phase of insulin release, abnormal pulsatility of basal insulin secretion, and increased glucagon secretion also accelerate the development of
T2DM [4, 5]. Although T2DM patients are generally
independent of exogenous insulin, they may need it
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when blood glucose levels are not well controlled
with diet alone or with oral hypoglycemic drugs. In
addition, people with T2DM are often accompanied
by complications, such as cardiovascular diseases,
diabetic neuropathy, nephropathy, and retinopathy.
Diabetes and its associated complications lower the
quality of people’s lives and generate enormous economic and social burdens [6].
Epidemiology
T2DM has become an observably global public
health problem. Analysis of recent statistical data reveals that T2DM has several new epidemiological
characteristics. Firstly, diabetes keeps a steady increase in developed countries, such as United States
and Japan. And it is worthy of note that T2DM has
become a serious issue at an alarming rate in developing countries. It is predicted that T2DM will continue to increase in the next twenty years, and more
than 70% of the patients will appear in developing
countries, with the majority of them being 45-64 years
old [7]. Even today, seven out of top ten countries
with the largest number of diabetes patients are lowor middle-income countries, including India, China,
Russia, Brazil, Pakistan, Indonesia, and Bangladesh
[7], among which the prevalence rates are 12.1% and
9.7% in India and China, respectively [8, 9]. Secondly,
although advancing age is a risk factor for T2DM,
rising rates of childhood obesity have resulted in
T2DM becoming more common in children, teenagers
and adolescents, which is a serious emerging of the
epidemic and a new public health problem of significant proportions [10].
Correlations with and influencing factors
on T2DM
Heritable genetic correlation. Genetic component: Although we have not completely elucidated the
pathophysiology of T2DM so far, it is the case that the
disease has a major genetic component. Higher concordance rates are found among monozygotic (96%)
than dizygotic (DZ) twins in some [11, 12] but not all
[13] twin studies, which has been a compelling evidence of a significant genetic component in T2DM.
Moreover, 40% of first-degree relatives of T2DM patients may develop diabetes, whereas the incident rate
is only 6% in the general population [14].
Susceptibility loci: In addition to a considerable
number of genetic components associated with
T2DM, segregation analysis also suggests the polygenic nature of T2DM. The susceptibility loci of T2DM
have been discovered by genome-wide association
studies (GWAS) since early 2007 [15-21]. Then, numerous GWAS conducted in different countries and
ethnic groups have reported linkage signals at the
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same or different chromosomes with T2DM, and have
successfully identified approximately 75 susceptibility loci related to T2DM. Examples of candidate genes
are KCNJ11 (potassium inwardly rectifying channel,
subfamily J, member 11), TCF7L2 (transcription factor
7–like 2, the strongest T2D locus identified to date),
IRS1 (insulin receptor substrate 1), MTNR1B (melatonin-receptor gene), PPARG2 (peroxisome proliferator-activated receptor gamma 2), IGF2BP2 (insulin-like growth factor two binding protein 2),
CDKN2A (cyclin-dependent kinase inhibitor 2A),
HHEX (hematopoietically expressed homeobox) and
FTO (fat mass and obesity associated) gene. van Exel
and his group found that low IL-10 production capacity is also associated with T2DM [22]. It is worth
highlighting that IL-10-1082A/G polymorphism is
associated with T2DM susceptibility in Asians, but
not in Europeans and Africans, which may be ascribable to various genetic background and environmental exposures [23]. Some important susceptibility loci
are listed in Table 1.
Table 1. Susceptibility loci associated with T2DM discovered
with GWAS.
Gene
KCNQ1
Gene Region
11p15.4
11p15.4
11p15.4
11p15.4
10q25.2
11p15.1
11p15.1
2q36.3
11q14.3
SNPs
rs2237897
rs2237895
rs231362
rs2237892
rs7903146
rs5219
rs5215
rs7578326
rs1387153
Population
Japanese
Chinese
European
Japanese
European
European
UK
European
European
P-Value
6.8×10-13
9.7×10-10
2.8×10-13
1.7×10-42
2.0×10-31
6.7×10-11
5.0×10-11
5.4×10-20
7.8×10-15
Ref.
[24]
[25]
[26]
[27]
[18]
[17]
[19]
[26]
[26]
IGF2BP2
3q27.2
3q27.2
rs4402960
rs6769511
European
European
8.9×10-16
9.0×10-16
[17]
[19, 24]
CDKN2A/B
9p21.3
9p21.3
9p21.3
rs564398
rs2383208
rs10811661
UK
Japanese
European
1.3×10-6
[19]
1.6×10-7
[28]
7.8 × 10-15 [17]
HHEX
10q23.33
10q23.33
3p25.2
3p25.2
rs1111875
rs5015480
rs1801282
rs17036101
European
European
European
European
5.7×10-10
1.0×10-15
1.7×10-6
7.5×10-6
TCF7L2
KCNJ11
IRS1
MTNR1B
PPARG2
[17]
[29]
[17]
[30]
Among these susceptible loci, KCNJ11 encodes
the islet ATP-sensitive potassium channel Kir6.2;
TCF7L2 regulates proglucagon gene expression and
produces glucagon-like peptide 1[31]; IRS1 has an
effect on insulin action [32]; MTNR1B is correlated
with endogenous ligand melatonin that mediates circadian rhythm and affects metabolic regulation [33];
PPARG2 encodes a transcription factor for adipocyte
differentiation [34]; IGF2BP2 is involved in pancreas
development, growth and stimulation of insulin action [34]; HHEX affects β cell development; and FTO
predisposes to diabetes through acting on BMI (Body
Mass Index) [35]. Meanwhile, many of these loci are
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Int. J. Med. Sci. 2014, Vol. 11
also therapeutic targets for the extensively used
pharmaceuticals of T2DM, for example, KCNJ11 and
PPARG2 are targets of sulphonylurea and thiazolidinedione classes of drugs widely used for the treatment of T2DM, respectively [36, 37]. Nevertheless,
there are still many unsorted loci for the T2DM
pathogenesis. We thus need to expand our current
biological knowledge to completely understand and
control T2DM.
Lifestyle factor correlation. A wide variety of
lifestyle factors are also of great importance to the
development of T2DM, such as sedentary lifestyle
[38], physical inactivity [39], smoking [40] and alcohol
consumption [41]. Substantial epidemiological studies
have shown that obesity is the most important risk
factor for T2DM, which may influence the development of insulin resistance and disease progression
[42]. Nearly 90% of diabetic patients develop T2DM
mostly relating to excess body weight according to the
World Health Organization (WHO, 2011). Furthermore, obesity is strongly inherited [43]. Pamidi et al.
demonstrated that obstructive sleep apnea (OSA), a
treatable sleep disorder that is pervasive among
overweight and obese adults, has become a novel,
modifiable risk factor relevant to insulin resistance
and glucose intolerance, and may influence on the
development of prediabetes (20%-67%) and T2DM
(15%-30%), independent of shared risk factors [44-46].
Several studies have indicated that OSA in T2DM
patients is much more prevalent (36%–60%) than in
the general population [47, 48].
In addition, diet is considered as a modifiable
risk factor for T2DM. Studies have shown that a
low-fiber diet with a high glycemic index is positively
associated with a higher risk of T2DM [49], and specific dietary fatty acids may affect insulin resistance
and the risk of diabetes in varying degrees [50]. Total
and saturated fat intake is associated with an increased risk of T2DM independently of BMI, but
higher intake of linoleic acid has the opposite effect,
especially among leaner and younger men [51]. Frequent consumption of processed meat, but not other
meats, may increase the risk of T2DM after adjustment for BMI, prior weight change, and alcohol and
energy intake [51]. Soft drinks have also been
bounded up with increased risk of T2DM [52] and
metabolic syndrome [53], because they are directly
associated with BMI [54].
Gut metagenome correlation. In some recent
studies, gut metagenome was shown to be a factor for
the development of T2DM [55]. Different kinds of gut
bacteria may play different roles in maintaining or
interacting with their environment. Two-stage metagenome-wide association study (MGWAS) suggested
that T2DM patients show a moderate degree of gut
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microbial dysbiosis, with various butyrate-producing
bacteria being decreased (Clostridiales sp. SS3/4, Roseburia intestinalis, Roseburia inulinivorans, Eubacterium
rectale and Faecalibacterium prausnitzii) and some opportunistic pathogens being increased (Bacteroides
caccae, Clostridium hathewayi, Clostridium ramosum,
Clostridium symbiosum, Eggerthella lenta and Escherichia
coli) [56, 57].
In T2DM patients, the gut microbiota presents
enrichment in membrane transport of sugars, methane metabolism, branched-chain amino acid
(BCAA) transport, xenobiotics degradation and metabolism, and sulphate reduction; and reduction in the
level of bacterial chemotaxis, flagellar assembly, butyrate biosynthesis and metabolism of cofactors and
vitamins. A study showed that seven of the
T2DM-enriched KEGG orthologues markers were
associated with oxidative stress resistance, including
nitric
oxide
reductase
(K02448),
putative
iron-dependent peroxidase (K07223), cytochrome c
peroxidase (K00428), catalase (K03781), peroxiredoxin
(K03386), Mn-containing catalase (K07217), and glutathione reductase (NADPH) (K00383), which were
not seen in control-enriched KEGG orthologues
markers [58]. In addition, it was found that 14 KEGG
orthologues markers, which were markedly
up-regulated in T2DM patients, were related to drug
resistance. These results demonstrated that T2DM
patients may have a more hostile gut environment
that stimulates defense mechanisms against microbes
and oxidative stresses.
There is a T2D classifier system based on gut
microbiota, in which the T2DM index is correlated
with the ratio of T2DM patients and this system provides accurate classification of T2D individuals [58].
For example, butyrate-producing bacteria may play a
protective role against several types of diseases, and
dysbiosis in T2DM patients may result from ‘functional dysbiosis’ rather than a specific microbial species.
Gut metagenomic markers show higher specificity for differentiation between T2DM cases and controls based on human genome variation, which may
be a promising complementary approach to monitor
gut health for risk assessment of this disease [59].
Vitamins and type 2 Diabetes. Vitamin D: Accumulating evidence supports that vitamin D may
have a potential role in the control of T2DM [60, 61],
as seasonal variation is found in glycemic status of
T2DM patients, in which hypovitaminosis D frequently occurred in the winter is likely to be associated with the aggravation of T2DM. A recent research
shows that vitamin D deficiency may have negative
effects on glucose intolerance, insulin secretion and
T2DM [62], either directly via vitamin D receptor
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(VDR) activation or indirectly via calcemic hormones
and also via inflammation [63, 64]. As both
1-α-hydroxylase and VDR are present in pancreatic β
cells, vitamin D has significant roles in the synthesis
and release of insulin [65]. Furthermore, vitamin D
has influence on the insulin sensitivity by controlling
calcium flux through the membrane in both β cells
and peripheral insulin-target tissues [66]. In addition,
vitamin D supplementation is recognized as a promising and inexpensive therapy, which may decrease
the risk of T2DM and improve glycemic parameters in
T2DM patients [67]. Therefore, it is seemingly that the
positive effects of vitamin D are correlated with its
action on insulin secretion and sensitivity as well as
on inflammation.
Vitamin K: Vitamin K has two naturally occurring forms, including phylloquinone (vitamin K1) and
menaquinones. Menaquinone-4 (vitamin K2) is considered as the active form of vitamin K in the bone
tissue and functions in maintaining bone quality [68]
and also as a transcriptional regulator of bone-specific
genes that acts through steroid and xenobiotic receptors (SXRs) to promote expression of osteoblastic
markers [69]. It plays a protective role in bone fractures, in which the substance can promote
γ-carboxylation of osteocalcin and induce production
and secretion of osteocalcin by osteoblasts or may
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stimulate bone formation through SXRs.
Besides, a recent survey indicates that vitamin
K1 provides benefits in glucose homeostasis, as higher
intake of vitamin K1 is correlated with greater insulin
sensitivity and glycemic status [70]. Because poor
glycemic control and bone quality may occur when
vitamin K is deficient, it is cardinal to exclude vitamin
K deficiency in T2DM patients. Several preclinical and
clinical observations show that vitamin K2 has effects
on bone quality and subsequent bone mechanical
strength in T2DM patients independently of increasing BMD (bone mineral density) [71, 72]. It is also
suggested that vitamin K2 may improve osteocyte
density and lacunar occupancy by viable osteocytes in
the cortical bone of glucocorticoid-treated or sciatic
neurectomized rats [73, 74]. In addition, vitamin K2
may down-regulate bone turnover and stimulate lamellar bone formation, and prevent an increase in
bone resorption with maintaince of bone formation
and prevent a decrease in lamellar bone formation in
glucocorticoid-treated rats [75]. Further studies are
required for the comprehensive assessment of the role
of vitamin K in the development of T2DM.
In summary, the above-mentioned susceptibility
loci and other influencing factors of T2DM are shown
in Figure 1.
Figure 1. A summary of the influencing factors and mechanism of T2DM. (A) Lifestyles; (B) Susceptibility loci; (C) Gut metagenome association;
(D) Vitamins. (E) The mechanism of T2DM.
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Figure 2. The complications of T2DM.
Complications
T2DM patients are more susceptible to different
forms of both short- and long-term complications. As
shown in Figure 2, the complications include macrovascular diseases (hypertension, hyperlipidemia,
heart attacks, coronary artery disease, strokes, cerebral vascular disease, and peripheral vascular disease), microvascular diseases (retinopathy, nephropathy, and neuropathy) and cancers.
Cardiovascular disease. Cardiovascular disease
is a primary cause of mortality and morbidity in both
prediabetes and T2DM, the potential mechanism for
which is oxidative stress that has important effects on
atherogenesis and may contribute to low-density
lipoprotein (LDL) oxidation [76]. Prevention of
premature cardiovascular events involves complex
interactive treatments with antihypertensives, lipid-lowering agents, and routine low-dose aspirin
administration [77].
Diabetic neuropathy. Diabetic neuropathy may
be associated with foot ulcers, amputations,
non-healing skin wounds, and sexual dysfunction
[12]. The neuropathy results in loss of protective sensation in the feet, which leads to callous formation,
ulceration and other injury, and may also result in the
infection of the skin (e.g. cellulitis) and/or bones of
the foot (e.g. osteomyelitis) and gangrene [77]. Sexual
dysfunction usually occurs in young-aged diabetic
patients because of oxidative stress in cavernous tissues [78].
Diabetic nephropathy. Diabetic nephropathy is
one of the most important microvascular complica-
tions, whose earliest manifestation is the presence of
minute amounts of urinary protein (microalbumin)
which can not be detected in routine urinalysis, but is
detectable by specific testing. If the detection can be
done in the earlier phase, the progression of
nephropathy can be prevented. This is, however,
frequently overlooked because of the unawareness
that the routine urinalysis lacks sensitivity in detecting microalbuminuria [77].
Diabetic retinopath. The retina is the most vascular region in the body, as it needs high oxygen to
convert light into electrical energy in the rods and
cones. Chronic hyperglycemia may cause microvascular damage to the retinal vessels, resulting in edema
and/or hemorrhage into the retina or the vitreous
humor because of vascular permeability. In fact, dysglycemia often occurs earlier than the diagnosis of
diabetes patients, because nearly 20% of newly diagnosed diabetes patients show evidence of retinopathy
[79].
Cancers. Epidemiologic evidence has demonstrated that diabetes may elevate the risk of cancer
such as colorectal cancer [80], liver cancer [81], bladder cancer [82], breast cancer [83], kidney cancer [84],
which varies depending on the subsites of specific
cancers. Mechanisms underlying the association of
T2DM with cancer risk are as follows: firstly, T2DM
and cancers usually share many risk factors such as
age, obesity, sedentary lifestyle, smoking, higher intake of saturated fats and refined carbohydrates, and
some psychology factors [85]. Secondly, hyperinsulinemia is one of the major characteristics of T2DM.
Meanwhile, it might promote carcinogenesis directly
[86] as it may promote the proliferation of colonic
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tumors in vitro and in experimental animals [87]. Besides, hyperinsulinemia may increase the level of
IGF-1 which has mitogenic and antiapoptotic actions
on cancer cells [88], and the plasma or serum level of
IGF-1 is also positively correlated with the risk of
cancers [89, 90].
Treatment of T2DM
Common non-insulin antidiabetic drugs. Biguanides: Biguanides are one of the major classes of
antidiabetic drugs, among which metformin is the
most common drug used in the first line therapy for
diabetes mellitus [91]. Metformin has been proven to
be efficacious in lowering blood glucose, increasing
insulin sensitivity, reducing cardiovascular [92] and
hypoglycemia risk [93], and is the only hypoglycemic
agent to improve macrovascular outcomes [94] and to
reduce mortality rates in T2DM patients [95]. The
glucose-lowering effect of metformin is mainly
through reducing hepatic glucose output such as
gluconeogenesis and glycogenolysis, and increasing
insulin-stimulated glucose uptake and glycogenesis in
skeletal muscle [96]. In addition, it is demonstrated
that metformin has important roles in activating
AMP-activated protein kinase (AMPK) which acts on
the expression of hepatic gluconeogenic genes [97]
and decreasing progression of impaired glucose tolerance in T2DM patients [98]. It is worthy of note that
metformin should be used cautiously in elderly diabetic patients owing to the concern of lactic acidosis,
gastrointestinal (GI) effects such as nausea, vomiting
diarrhea and flatulence, the reduction of calorie intake, and weight loss. Besides, metformin should not
be used in patients with chronic or acute renal insufficiency, and must be terminated when creatinine
levels reach 1.4 mg/dL (120 µmol/L) in women or 1.5
mg/dL (130 µmol/L) in men [99].
Sulfonylureas: Sulphonylureas are second line
agents widely used in the treatment of T2DM patients
who are not severely obese, which act directly on the
islet β cells to close ATP-sensitive K+ channels and
stimulate insulin secretion [100]. They remain effective until they reach their targets when used alone or
combined with other anti-hyperglycemic drugs [1],
but they are dependent on the presence of enough β
cells with sufficient functional reserve. The major
acute adverse reaction of sulphonylureas is higher
rate of hypoglycemia [101], especially in older adults
with impaired renal function, hepatic dysfunction,
and those with poor oral intake, or alcohol abuse, or
caloric restriction and so on [102]. Sulphonylurea-induced hypoglycemia may be exacerbated by
interaction with a variety of drugs, such as aspirin,
oxidase inhibitors, and phenylbutazone [1]. In addition, sulfonylureas can cause weight gain. The use of
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sulfonylureas, however, seems to have no obvious
influence on cardiovascular diseases [103].
Thiazolidinediones: Thiazolidinediones (TZDs)
are a class of insulin sensitizers, including troglitazone, rosiglitazone, and pioglitazone. They are peroxisome proliferator-activated receptor γ (PPAR-γ)
ligands which control normal skeletal muscle and
hepatic insulin sensitivity [104]. The TZDs have more
durable action to regulate hyperglycemia than sulfonylureas and metformin, and do not increase the
risk of hypoglycemia when used as monotherapy [1].
TZDs are efficacious in combined therapy with other
classes of antidiabetic agents, especially in combination with insulin to reduce the high insulin dosage
and improve glycemic control in T2DM [1]. Moreover,
preliminary clinical studies have demonstrated that
TZDs and metformin, two different classes of drugs,
can be used together to cooperatively lower blood
glucose activity [1]. However, TZDs exhibit several
negative effects in the treatment for T2DM, including
an increased risk of bladder cancer [105], weight gain
and fluid retention leading to edema. Even though
pioglitazone is well tolerated in the treatment of elderly patients with renal impairment and does not
cause hypoglycemia, its use should be avoided in
older patients with congestive or class III-IV heart
failure. Rosiglitazone and troglitazone have been
withdrawn from the market considering the increased
risk of myocardial infarction [106] and idiosyncratic
hepatotoxicity [107], respectively.
α-Glucosidase inhibitors (AGIs): α-Glucosidase
inhibitors (AGIs), including acarbose, voglibose and
miglitol, are markedly effective for postprandial hyperglycemia. They inhibit intestinal mucosal enzyme
(α-glucosidase) which converts complex polysaccharides into monosaccharides, thus decreasing carbohydrate absorption. Voglibose can significantly improve glucose tolerance [108] and acarbose (precose)
would reduce the risk of cardiovascular diseases such
as acute myocardial infarction in T2DM [109]. Side
effects such as abdominal bloating, diarrhea and flatulence are always observed after the use of this class
of drugs. Their use should be limited in older adults
because of gastrointestinal side effects and frequent
dosing should be avoided in patients with significant
renal impairment [110].
Incretin-based therapies: Incretins are hormones
that stimulate insulin secretion and suppress postprandial glucagon secretion in a glucose-dependent
manner. They are secreted from intestinal endocrine
cells, including glucose-dependent insulinotropic
polypeptide (GIP) and glucagon-like peptide-1
(GLP-1). Incretin-based therapy is ideal for T2DM
management because of its efficacy, good tolerability,
low risk of hypoglycemia, and weight loss [111].
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Furthermore, it may also have positive effects on inflammation, sleep, cardiovascular and hepatic health,
and central nervous system.
GLP-1 receptor agonists: GLP-1 receptor agonists, including exenatide and liraglutide, can reduce
hemoglobin A1c (HbA1c) levels by 0.8% to 1.5% [112].
GLP-1 receptor agonists are effective in the regulation
of glucose metabolism, such as stimulating insulin
production, inhibiting glucagon release, slowing nutrient absorption, and increasing feelings of satiety
[94]. Because this class of agents is not specifically
designed for older diabetic patients, there is no statistical difference in efficacy and safety profiles between
elderly and younger patients [113]. Here, some antidiabetic agents for the treatment of T2DM are summarized in Table 2.
Table 2. Representative antidiabetic agents for the management of patients with T2DM
Class
Biguanides
Drug (s)
Metformin
Target
AMP-kinase
Sulfonylureas
Glyburide/
Glipizide/
Gliclazide/
Glimepiride
Troglitazone/
Roziglitazone/
Pioglitazone
ATP-sensitive,
K+ channels
TZDs
AGIs
Acarbose/
Miglitol/
Voglibose
GLP-1 receptor agonists Exenatide/
Liraglutide
PPAR-γ
α-glucosidase
GLP-1 receptors
Action (s)
blood glucose↓
insulin sensitivity↑
cardiovascular risk↓
hypoglycemia risk↓
insulin secretion↑
Disadvantages
GI side effects
lactic acidosis
Vitamin B12 and
folate deficiency
Ref.
[92, 93, 110, 114]
hypoglycemia
weight gain
[100, 101, 114]
insulin sensitivity↑
hypoglycemia risk↓
glycemic control↑
carbohydrate absorption↓
bladder cancer risk↑
weight gain
edema
GI side effects
dosing frequency
[1, 104, 105]
insulin secretion↑
glucagon secretion↓
satiety↑
hypoglycemia risk↓
GI side effects
acute pancreatitis
renal dysfunction
thyroid C-cell tumors in rodents
[110, 112]
Currently, treatment guidelines generally recommend the use of metformin monotherapy as initial
treatment. When T2DM patients cannot be well controlled by lifestyle and single oral antidiabetic drugs,
it may be necessary to consider combination therapy
with two or more antidiabetic drugs such as a thiazolidinedione plus metformin or a dipeptidyl peptidase-4 (DPP-4) inhibitor plus metformin [115, 116].
The combination therapy has several advantages over
monotherapy: (1) greater efficacy with lower-dose; (2)
reduced risk of negative effect; (3) lower costs; (4)
improved medication concordance [117].
Insulin and insulin analogues. Insulin, the most
effective anti-hyperglycemic agent, was discovered by
Banting and Best in 1921. Since then, it has brought
about great advances in the treatment of T2DM. Insulin therapy can provide effective glycemic control
even when oral antidiabetic medicines are inadequate,
and can improve many of the metabolic abnormalities
in T2DM patients. The mechanism underlying the
reduction of glucose concentrations by insulin is
mainly through suppressing hepatic glucose production, increasing postprandial glucose utilization, and
improving abnormal lipoprotein composition. Moreover, insulin therapy can improve insulin sensitivity
and β-cell secretary function by the reduction of hyperglycemia, thus decreasing or eliminating the effects of glucose toxicity. In addition, it can suppress
[110]
ketosis and contribute to delaying diabetic complications. Insulin has four injectable forms, including
rapid acting, short acting, intermediate acting and
long acting, among which the long acting forms are
least likely to cause hypoglycemia.
Insulin analogues have different pharmacokinetic profiles, compared to that of regular insulin, and
their onset and duration of action range from rapid to
prolonged. At present, rapid-acting insulin analogues
(insulin lispro and insulin aspart) and long-acting
insulin analogues (insulin glargine and detemir) are
available [118]. Long-acting insulin analogues can
provide a prolonged duration of action and reduce
the risk of hypoglycaemic events, especially nocturnal
events [119].
When lifestyle changes and oral antidiabetic
agents fail to achieve adequate glycemic control in
T2DM patients, it is generally required for the patients
to initiate insulin therapy. Numerous reviews introduced the effectiveness of combination therapy with
insulin and oral antidiabetic agents in T2DM patients
[120, 121]. For example, Baruah et al. used GLP-1 analogue and insulin as a fixed dose combination (FDC)
therapy in a wide range of population, and demonstrated that fasting and postprandial glucose could be
effectively controlled and the therapy was well tolerated [122].
New therapeutic strategies. Although oral antihttp://www.medsci.org
Int. J. Med. Sci. 2014, Vol. 11
diabetic agents and insulin are currently used for the
treatment of T2DM and have brought about promising outcomes, problems still exist such as inadequate
efficacy and adverse effects. We thus need to examine
novel therapy strategies.
SGLT2
inhibitors:
Sodium
glucose
co-transporter type 2 (SGLT2) inhibitors are a new
class of glucose-lowering agents which prevent the
reabsorption of renal-filtered glucose back into the
circulation [123] and increase urinary glucose elimination, thus lowering blood glucose levels [124]. They
have been shown to be effective in reducing HbA1c,
fasting plasma glucose (FPG), systolic blood pressure,
bodyweight, as well as hyperglycaemia [125].
Dapagliflozin, one of the most advanced SGLT2 inhibitors, has been confirmed effective either as monotherapy [126] or as add-on therapy with metformin
[127] and insulin [128]. Adverse effects observed in
the treatment of T2DM patients with dapagliflozin
include genital infections and the occurrence of breast
and bladder cancer [129]. Long-term observational
studies are, therefore, needed to examine possible
negative effects.
DPP-4 inhibitors: Dipeptidyl peptidase-4
(DPP-4) inhibitors can improve the action of endogenous active GLP-1 and GIP by blocking its degradation by DPP-4 enzyme [130]. They are effective in the
protection of pancreatic β cells and promotion of
normal glucagon secretion, thus inhibiting the progression of T2DM. DPP-4 inhibitors are well tolerated
because they play pivotal roles in cardiovascular
protection and anti-arteriosclerotic action, with few
gastrointestinal side effects and weight neutrality
[131]. So far, available DPP-4 inhibitors include
vildagliptin, sitagliptin, saxagliptin and linagliptin,
which have been assessed in a variety of clinical
studies
about
their
pharmacokinetics/pharmacodynamics, safety, efficacy, and tolerability [132]. Vildagliptin, one of the representative
drugs, shows long-term advantages in the preservation of α- and β-cell functions, decrease in fasting lipolysis in adipose tissue, reduction in total cholesterol
and lipotoxicity, and triglyceride storage in non-fat
tissues such as muscle, pancreas and liver, with little
drug interactions [133]. Sitagliptin, another leading
agent, available for use in Japan for the past few years,
is now used in many T2DM patients with low insulin
secretory capacity [134], whose efficacy and safety
have been confirmed in many clinical practices [135].
Lixisenatide: Lixisenatide (Lyxumia®), a glucagon-like peptide (GLP)-1 receptor agonist, was approved for marketing by the European Medicines
Agency in February 2013. Lixisenatide can activate the
GLP-1 receptor, thus contributing to increasing insulin secretion, inhibition of glucagon secretion and de-
1192
creasing gastrointestinal motility to promote satiety
[136]. In the GetGoal study program, HbA1c, FPG,
and postprandial plasma glucose (PPG) were effectively decreased by the use of lixisenatide. Furthermore, lixisenatide reduced bodyweight and had
therapeutic effects on glycemia when used as monotherapy or combined therapy with insulin and oral
antidiabetic drugs. Nowadays, the primary combined
therapy of lixisenatide seems to be with basal insulin,
and clinical development as a combination product
with insulin glargine (Lantus®) is still undergoing.
GPR40 agonists: G protein-coupled receptor 40
(GPR40) is a free fatty acid (FFA) receptor and
Gq-type, Gq-coupled G protein-coupled receptor
which is highly expressed in pancreatic β-cells [137].
The stimulation of GPR40 with FFAs leads to insulin
secretion through β-cell-specific signaling pathway,
which can be inhibited by the treatment with small
interfering RNA [138]. A large number of chemical
compounds which can act as GPR40 agonists exhibit
glucose-dependent insulin secretion in vitro and in
vivo, among which TAK-875 can reduce fasting plasma glucose and HbA1c levels in clinical trials [139].
Recently, Tanaka and his colleagues reported three
novel GPR40 agonists AS2031477, AS1975063 and
AS2034178, which could improve both acute glucose-dependent insulin secretion and chronic
whole-body glucose metabolism [140]. Among these
GPR40 agonists, AS2034178 has been shown to reduce
microvascular complications, thus it has a therapeutic
potential to improve the prognosis of T2DM patients.
In conclusion, GPR40 agonists represent a new class
of drugs in the treatment of T2DM, especially
AS2034178 is the most promising candidate.
Nitrate/Nitrite: Nitric oxide (NO) is a simple
ubiquitous molecule which can play significant roles
in almost every biological system. It is synthesized
from L-arginine by NO synthase (NOS) enzymes including neuronal (nNOS), inducible (iNOS), endothelial (eNOS), and mitochondrial (mtNOS) NOS. In the
body, nearly 90% of NO is converted to nitrate (NO3-),
a stable end-product of NO [141]. It has been demonstrated that NO3- and nitrite (NO2-) may have some
therapeutic implications, such as decreasing blood
pressure [142], reducing oxidative stress [143], and
reducing oxygen consumption during exercise. It is
also demonstrated that inorganic nitrate therapy can
reduce visceral fat accumulation, lower serum triglycerides and normalize a disturbed glucose tolerance in eNOS deficient mice [144]. These findings
suggest the roles of NO3- and NO2- in the prevention
and treatment of T2DM for reduced weight in
long-term NO3- therapy [145]. However, harmful effects exist in the NO3-/NO2- therapy: high levels of
plasma NO3- (1) increase arterial pressure; (2) may
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Int. J. Med. Sci. 2014, Vol. 11
cause early onset of hypertension; (3) increase incidence of diabetes; (4) induce kidney dysfunction; and
(5) produce hypothyroidism [146]. All in all,
NO3-/NO2- shows potential roles in new therapeutic
applications for human health, and also does potential
human risks. NO3-/NO2- derived from natural sources
such as vegetables may be one of the ideal choices.
Further investigations are necessary in this field, especially in the identification of individuals who may
benefit from the NO3-/NO2- therapy.
Stem cell educator therapy: Evidence has suggested that T2DM patients always display multiple
immune dysfunctions and chronic metabolic inflammation. Researches have shown that monocytes/macrophages may be main players which contribute to these chronic inflammations and insulin
resistance in T2DM patients [147]. Stem cell educator
therapy, a novel technology, is designed to control or
reverse immune dysfunctions [148]. The procedure
includes: collection of patients’ blood circulating
through a closed-loop system, purification of lymphocytes from the whole blood, co-culture of them
with adherent cord blood-derived multi-potent stem
cells (CB-SCs) in vitro and administration of the educated lymphocytes (but not the CB-SCs) to the patient’s circulation [149] (Fig. 3). Current phase I/
phase II studies suggest the safety and therapeutic
efficacy of this kind of therapy in T2DM, with remarkably increased insulin sensitivities and notable
improvement of metabolic control in T2DM patients
[150]. This new method exhibits great benefits in improving treatment and cure for T2DM, particularly in
early-stage diabetic patients, which may help to cope
with diabetes-associated complications and improve
the quality of their life.
Anti-inflammatory treatment: It has been
demonstrated that apparent changes in the immune
1193
system occur in T2DM, especially in adipose tissue,
pancreatic islets, the liver, the vasculature and circulating leukocytes [151], which include altered levels of
specific cytokines and chemokines, the number and
activation state of different leukocyte populations,
increased apoptosis and tissue fibrosis. These changes
indicate that inflammation plays a pivotal role in the
pathogenesis of T2DM and its complications. Salicylates and interleukin-1 antagonists are the representative drugs with immunomodulatory effects in the
treatment of T2DM patients, which can lower blood
glucose levels and reduce severity and prevalence of
the associated complications [152, 153]. Recently,
phase III clinical trials are ongoing [154].
Antioxidant therapy: Antioxidant therapy may
be another new effective way for the treatment of
T2DM patients [155], which may play important roles
in lowering the risk of developing diabetes and its
complications. A variety of antioxidants, such as
vitamins, supplements, plant-derived active substances and drugs with antioxidant effects, have been
used for oxidative stress treatment in T2DM patients.
Vitamin C, vitamin E and β carotene are ideal supplements against oxidative stress and its complications [76]. For example, vitamin C can decrease fasting
plasma insulin and HbA1c level, improve insulin action, and β carotene may reduce oxidative LDL [156].
Plants which contain substances with antioxidant
properties such as monoterpenes, cinnamic acids,
coumarins, flavonoid, diterpenes, phenylpropanoids,
triterpenes, tannins and lignin can provide therapeutic effects in the treatment of T2DM [76]. Drugs with
antioxidant properties, for example, α-lipoic acid and
carvedilol, also have antioxidant effects in T2DM
[156].
Figure 3. The procedure of stem cell educator therapy.
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Int. J. Med. Sci. 2014, Vol. 11
Risk assessment
Statistically, about 50% of people with diabetes
remain undiagnosed and approximately 20-30% patients usually have already developed complications
before being diagnosed [157]. An alternative screening approach is thus urgently required for the earlier
diagnose of T2DM. At present, a variety of risk assessment tools based on self­assessed, biochemical
measures or genetic markers have been developed for
the prediction of T2DM, which are more practical and
valuable than conventional blood glucose screening
test, so that interventions can be applied to those with
impaired glucose tolerance to delay the onset of
T2DM.
Prediction models with noninvasive measures.
Noninvasive measures require information about age,
sex, height, waist circumference, BMI, ethnicity, history of hypertension and prevalent/latent diabetes,
medication use, physical activity, and consumption of
berries alcohol, coffee, whole grains, fruits, vegetables, red meat and so on [158, 159]. FINDRISC (Finnish Diabetes Risk Score) questionnaire, the most
commonly used method [160], is designed to
self-assess the risk on the basis of seven questions,
which has a good validity in the prediction of future
diabetes onset over a 10-year period [158]. The other
approach is based on the data which are routinely
available to the general practitioner, for example, the
CRS or the QDScore® (ClinRisk, Leeds, UK) [161-163].
Researches have demonstrated that noninvasive
screening tools are more cost-effective than a blood
test as a first stage screening, and risk scores show
good sensitivity and specificity for the identification
of prevalence or incident of impaired glucose regulation or T2DM [164].
Prediction models including biochemical
measure. Biochemical testing plays an essential role in
the identification of individuals with high risk for
developing T2DM [165, 166]. It usually involves a
multi-step procedure: firstly, simple questionnaires or
noninvasive measures; then, measurement of biochemical makers in prescreened individuals.
Many studies have been conducted to evaluate
the prediction models for metabolic syndromes in
terms of sensitivities, specificities, and predicted values along with basic noninvasive information. Generally, they include concentrations of blood lipids (e.g.
high density lipoprotein cholesterol, triglycerides),
plasma glucose (either fasting or 2-hour), blood
pressure and waist circumference [167-169]. Among
them, triglyceride and high density lipoprotein cholesterol can be easily obtained in clinical practice and
can slightly increase the predictive value. In particular, fasting plasma glucose can obviously improve the
1194
predictive value based on noninvasive measures.
Some novel biochemical markers include
C-reactive protein, liver enzymes and so on. In the
European Prospective Investigation into Cancer and
Nutrition-Potsdam (EPIC-Potsdam) Study, C-reactive
protein has not shown added prognostic information
beyond the extended prediction model, whereas liver
enzymes with concentrations of blood lipids can obviously improve prediction beyond the noninvasive
parameters and measures of glycemia [170]. Besides, a
risk score from Taiwan shows that white blood cell
count can also improve prediction, although the accuracy of the derived score is low [171].
Prediction models involving genetic maker. A
large number of genetic variants have been investigated for the prediction value of T2DM [172, 173], and
they marginally improved prediction beyond noninvasive characteristics in those studies. Because the
accuracy of prediction relies on many factors such as
the number of genes involved, the frequency of the
risk alleles, and the risks correlated with the genotypes [174, 175], many additional common variants
with small effect sizes or rare variants with stronger
effect sizes must be further identified. It is always a
time-consuming and painstaking project to identify
novel diabetes genes by GWAS, which requires many
cases for sufficient statistical power to ensure a very
modest increase in risk of each risk allele. Even
though these have been done successfully, it still
needs to consider how the information can be provided to patients and whether it will encourage people to adopt healthy lifestyles and medical interventions.
Lifestyle intervention for prevention of
T2DM
Physical activity interventions. Nowadays,
physical inactivity has been considered as one of the
biggest public health problems worldwide [176]. It is
demonstrated that physical activity may contribute to
30–50% reduction in the development of T2DM [177].
Physical activity interventions can improve glucose
tolerance and reduce the risk of T2DM [178], because
it simply help achieve weight loss [179]. Any types of
physical activity should be acceptable to the majority
of the population. For example, walking, the most
popular choice of physical activity, has been shown to
reduce the relative risk of T2DM by 60% when walk
for 150 min/week, compared to walking for <60
min/week [180]. It is widely advocated to keep a
daily step, which is an effective self-regulatory strategy to successfully promote increased physical activity. For people who have difficulty in walking because
of joint problems, other forms of physical activity, for
example, cycling, swimming or gym-based activities,
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Int. J. Med. Sci. 2014, Vol. 11
should be encouraged.
Healthy eating. Diabetes prevention studies
have demonstrated that diet composition is another
important factor to prevent the development of
T2DM. Epidemiological studies have suggested that
the risk of diabetes can be increased or decreased
owing to dietary factors. The dietary factors which
may increase the diabetes risk are consuming excessive amounts of refined grains, sugar-sweetened
beverages, red and processed meat and alcohol, and
those with the opposite effects are the intake of
whole-grain cereal, vegetables, dairy, legumes, nuts,
independently of body weight change [181–183].
A large number of prevention studies concerning
dietary factors have been conducted in many countries during the past several years. Studies from China, Japan and India aimed at examining the effects of
reducing fat, refined carbohydrates and alcohol and
increasing fibre intake on the development of T2DM
[184-186]. The Finnish Diabetes Prevention Study
(DPS) advocated decreasing total and saturated fat
intake and increasing fibre density in the diet [187]. In
the Diabetes Prevention Program (DPP), dietary goals
were to reduce total fat and energy intake [188]. A
Mediterranean diet characterized by a high intake of
vegetables, fruit, legumes, extra virgin olive oil, nuts,
fish, whole grains and red wine also showed a remarkable decrease in the incidence of diabetes in a
Spanish study [189].
Even though diet is quite variable owing to food
availability, personal preferences and different cultures, a general rule can be derived: a high intake of
vegetables, fruits and fat from vegetables with low
saturated fat content should be preferred; nuts, legumes, dairy and fish should be taken as supplement
for enough body protein; grain products unrefined
and with high natural fiber content should be mainly
chosen; red meat and highly processed foods should
be limited (e. g., processed meat, confectionery).
Behavior change interventions. It has been
shown that behavior change interventions can prevent or delay the development of T2DM for people
with high risk [190]. For instance, the DPS and DPP
demonstrated that changes in diet or physical activity
could reduce the diabetes incidence by almost 60% in
4 years [98, 191]. Vermunt group took behavior
change techniques including motivational interviewing, filling out decisional balance sheets, goal setting,
developing action plans, barrier identification, relapse
prevention [192]. However, barriers existed for the
achievement of lifestyle change, one of which is continuity. For the weight loss and dietary improvement,
it is considerably difficult to resist temptation to
snacks, which needs to seek good techniques to control internal and external stimuli [193]. Examples for
1195
the stimulus control are encouraging people to avoid
cues for snacks storage [193] and to engage in social
support [194, 195]. We can also identify future
high-risk situations through monitoring psychological
causes and habitual behavior.
Obesity management. Obesity is one of the most
important risk factors for T2DM, whose basic cause is
an imbalance between energy intake and expenditure
[196]. Adipose tissue, particularly of the tissue surrounding internal organs (e.g. visceral fat) can secrete
various proinflammatory adipokines [197], and the
secretion of these cytokines will be changed if the
adipose tissue mass increase, this will contribute to
T2DM because of metabolic disturbances [198]. WHO
has identified several lifestyle-improving factors to
avoid obesity risk, including increased intake of high
dietary fiber, reduced intake of energy-dense, micronutrient-poor foods and regular physical activity.
Weight reduction may have effects on diabetes incidence, as seen in the DPP study, each kilogram of
weight loss is correlated with a 16% reduction in the
development of T2DM [199]. Weight reduction thus
seems to be beneficial in the prevention of T2DM, at
least in the short term [200]. Foods with low energy
density, such as vegetables and fruits, are advised to
increase satiety so that they can reduce total energy
intake and achieve weight reduction [201]. A meta-analysis suggests that a habitual energy imbalance
of about 50–100 kcal per day may contribute to the
gradual weight gain [202], however, modest and sustained changes in lifestyle could lighten or reverse this
status [202]. It is, therefore, more acceptable for people
to change gradually in diet or activity rather than
dramatically. These strategies require further investigations for the establishment of efficient prevention
and control of T2DM.
Conclusions
T2DM and its related complications impose
heavy health burdens worldwide and there have been
not effective measures to fully cope with the diseases.
The main cause of the diabetes epidemic is the interaction between genetic and environmental risk. A
number of other factors are also attributable to the
diseases. Whereas most antidiabetic agents have
shown beneficial effects when used as monotherapy
or combination therapy, they are also associated with
negative effects, such as weight gain, hypoglycemia,
gastrointestinal effects or cardiovascular disease. With
increasing incidence of T2DM, searching an ideal
therapy becomes one of the top priorities in combating this disease. To date, several therapeutic strategies
have been developed, such as the use of SGLT2 inhibitors, DPP-4 inhibitors and GPR40 agonists. Above
all, stem cell educator therapy opened avenues to
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Int. J. Med. Sci. 2014, Vol. 11
develop new therapeutic strategies in the treatment of
T2DM, with safety and high therapeutic efficacy.
Further investigations should focus on (1) the exact
mechanism contributing to T2DM and its related
complications; (2) effective intervention trials and
prevention measures to avoid the occurrence of this
disease; (3) earlier diagnosis for earlier treatment; (4)
novel drugs with more beneficial effects and less adverse effects, so as to conquer this disease and improve the quality of life and overall life span.
Acknowledgments
We gratefully acknowledge the support by the
Program for Zhejiang Leading Team of Science and
Technology Innovation (2011R50021) and Social Development Project of Zhejiang Province (2011C23004)
and Zhejiang Provincial Natural Science Foundation
of China (LY12B02019).
Competing Interests
The authors have declared that no competing
interest exists.
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Author biography
Dr. Yanling Wu is a professor in
Molecular Immunology and now heads the Cellular
and Molecular Immunology Research Group. She
received Master and Doctoral degrees in Applied Life
Science in 2003 and in Medicine Science in 2006, respectively, from Tohoku University, Japan. After that,
she entered to Professor Minato’s group of School of
Medicine, Kyoto University, Japan, as a senior researcher working in the field of molecular immunology. Her current researches focus on understanding
the molecular mechanisms of gene regulation related
to diseases by immune inhibitory receptors. Dr. Wu
have given oral presentations in international conferences and published related papers.
Yanping Ding received her
bachelor’s degree in biological sciences from Zhejiang
University of Chinese Traditional Medicine, China.
Since graduation, she has been working in Zhejiang
Center of Disease Control and Prevention, China. Her
research mainly focuses on the field of Molecular
Immunology under the guidance of Prof. Yanling Wu.
Yoshimasa Tanaka received his
Ph. D in Hokkaido University Graduate School of
Agriculture with a specialization in Enzymology and
Biochemistry. After graduation, he continued his research in the field of Immunobiology. Since 2008, he is
an associate professor and works in the Center for
Innovation in Immunoregulative Immunology and
Therapeutics that belongs to the Kyoto University
Graduate School of Medicine.
http://www.medsci.org
Int. J. Med. Sci. 2014, Vol. 11
1200
Dr. Wen Zhang is a full professor
with 25 years of research and teaching experience in
Bioorganic Chemistry and Chemical Biology. Dr.
Zhang earned his doctorate degree in Bioorganic
Chemistry from East China University of Science and
Technology, China. Then, he entered Professor
Ohrui’s Lab of Tohoku University, Japan, working in
the field of molecular recognition as a JSPS postdoctoral fellow. After that, he moved to Kyoto University,
Japan, to join Professor Sugiyama’s Chemical Biology
group as a COE and JST research fellow working on
biology and chemistry of polyamide-nucleic acids
interaction. Now, Dr. Zhang has a special interest in
elucidating the gene regulation mechanisms with
small organic molecules and the development of
gene-targeted drug. His group formed in 2008 and
established an extremely fruitful collaboration with
Prof. Sugiyama's Group in order to better pursue aspects of gene-targeted drug research. To date, Dr.
Zhang has published better papers as the
first/corresponding author in excellent Journals including JACS, JASN, ChemBioChem, Chem & Biol,
ChemMedChem, Int J Biol Sci etc.
http://www.medsci.org